UZH-Logo

Maintenance Infos

JAK2 as a novel mediator of the pro-fibrotic effects of TGFβ in systemic sclerosis


Dees, Clara; Tomcik, Michal; Palumbo-Zerr, Katrin; Akhmetshina, Alfiya; Beyer, Christian; Lang, Veronika; Horn, Angelika; Zerr, Pawel; Zwerina, Jochen; Gelse, Kolja; Distler, Oliver; Schett, Georg; Distler, Jörg H W (2012). JAK2 as a novel mediator of the pro-fibrotic effects of TGFβ in systemic sclerosis. Arthritis and Rheumatism, 64(9):3006-3015.

Abstract

OBJECTIVE.: Tissue fibrosis caused by a pathological activation of SSc fibroblasts is a major hallmark of systemic sclerosis (SSc). The aims of the present study were to investigate whether JAK2 contributes to the pathologic activation of fibroblasts in SSc and to evaluate the anti-fibrotic potential of JAK2 inhibition for the treatment of systemic sclerosis. METHODS.: Activation of JAK2 in human skin and in experimental fibrosis was determined by immunohistochemistry. JAK2 signaling was inhibited with the selective JAK2 inhibitor TG 101209 or by siRNA. Bleomycin-induced dermal fibrosis and tight-skin 1 (Tsk-1) mice were used to evaluate the anti-fibrotic potential of a specific JAK2 inhibition in vivo. RESULTS.: Increased activation of JAK2 was detected in the skin of SSc patients, particularly in fibroblasts. The activation of JAK2 was TGFβ dependent and persisted in cultured SSc fibroblasts. Inhibition of JAK2 reduced the basal collagen synthesis selectively in SSc fibroblasts but not in resting healthy dermal fibroblasts. Moreover, inhibition of JAK2 prevented the stimulatory effects of TGFβ on fibroblasts. Treatment with TG 101209 did not only prevent bleomycin-induced fibrosis, but also effectively reduced skin fibrosis in Tsk-1 mice. CONCLUSION.: We demonstrated that JAK2 is activated in a TGFβ dependent manner in SSc. Considering the potent anti-fibrotic effects of JAK2 inhibition, our study might have direct translational implications, because inhibitors of JAK2 are currently evaluated in clinical trials for myeloproliferative disorders and would be also available for evaluation in SSc patients.

OBJECTIVE.: Tissue fibrosis caused by a pathological activation of SSc fibroblasts is a major hallmark of systemic sclerosis (SSc). The aims of the present study were to investigate whether JAK2 contributes to the pathologic activation of fibroblasts in SSc and to evaluate the anti-fibrotic potential of JAK2 inhibition for the treatment of systemic sclerosis. METHODS.: Activation of JAK2 in human skin and in experimental fibrosis was determined by immunohistochemistry. JAK2 signaling was inhibited with the selective JAK2 inhibitor TG 101209 or by siRNA. Bleomycin-induced dermal fibrosis and tight-skin 1 (Tsk-1) mice were used to evaluate the anti-fibrotic potential of a specific JAK2 inhibition in vivo. RESULTS.: Increased activation of JAK2 was detected in the skin of SSc patients, particularly in fibroblasts. The activation of JAK2 was TGFβ dependent and persisted in cultured SSc fibroblasts. Inhibition of JAK2 reduced the basal collagen synthesis selectively in SSc fibroblasts but not in resting healthy dermal fibroblasts. Moreover, inhibition of JAK2 prevented the stimulatory effects of TGFβ on fibroblasts. Treatment with TG 101209 did not only prevent bleomycin-induced fibrosis, but also effectively reduced skin fibrosis in Tsk-1 mice. CONCLUSION.: We demonstrated that JAK2 is activated in a TGFβ dependent manner in SSc. Considering the potent anti-fibrotic effects of JAK2 inhibition, our study might have direct translational implications, because inhibitors of JAK2 are currently evaluated in clinical trials for myeloproliferative disorders and would be also available for evaluation in SSc patients.

Citations

22 citations in Web of Science®
23 citations in Scopus®
Google Scholar™

Altmetrics

Downloads

0 downloads since deposited on 11 Jul 2012
0 downloads since 12 months

Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Rheumatology Clinic and Institute of Physical Medicine
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:2012
Deposited On:11 Jul 2012 07:38
Last Modified:05 Apr 2016 15:52
Publisher:Wiley-Blackwell
ISSN:0004-3591
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:10.1002/art.34500
PubMed ID:22549363
Permanent URL: http://doi.org/10.5167/uzh-63274

Download

[img]
Content: Accepted Version
Filetype: PDF - Registered users only
Size: 1MB
View at publisher

TrendTerms

TrendTerms displays relevant terms of the abstract of this publication and related documents on a map. The terms and their relations were extracted from ZORA using word statistics. Their timelines are taken from ZORA as well. The bubble size of a term is proportional to the number of documents where the term occurs. Red, orange, yellow and green colors are used for terms that occur in the current document; red indicates high interlinkedness of a term with other terms, orange, yellow and green decreasing interlinkedness. Blue is used for terms that have a relation with the terms in this document, but occur in other documents.
You can navigate and zoom the map. Mouse-hovering a term displays its timeline, clicking it yields the associated documents.

Author Collaborations